The two specific aims of this component of the program project reflect two approaches to reducing the cariogenicity of dental plaque. The first involves increasing our knowledge of bacterial stress responses of oral bacteria. In dental plaque, bacteria are regularly subjected to multiple oxidative and other stresses. Acid adaptation in particular is considered to be key virulence attribute of cariogenic bacteria. The second specific aim also is oriented to reducing acid tolerance of plaque bacteria, specifically be use of weak acids able to act as transmembrane proton conductors at low pH values. The first specific aim has three main subcomponents. One derives from our recent finding that acid adaptation by oral streptococci involves changes in fatty acid composition of the cell membrane, mainly a shift to long, mono-unsaturated fatty acids. This shift is likely to affect proton permeability of the membrane and also the workings of various membrane enzymes including the H+-ATPase, which is known to require associated lipids for full activity. The second subcomponent is concerned with production of chaperonins by oral bacteria in response to environmental stress. It continues previous work on the roles of DnaK, HrcA and GroEL in acid adaptation and connects to other projects in considering chaperonin production in response to weak-acid stress and in mutants with altered profiles of membrane fatty acids. The third subcomponent considers the role of catalase produced by plaque bacteria in tolerance of oxidative stress. The second specific aim interdigitates with studies in Dr. Bowen's laboratory on use of weak acids to control caries and to make fluoride more effective as an anti-caries agent. Our focus will be on the cell membrane and obtaining a clearer view of how weak acids act to increase proton permeabilities of bacterial membranes and cells. The enhancement of proton permeabilities of bacterial membranes and cells. The enhancement of proton permeabilities reduces acid tolerance, and presumably, carcinogenicity. We are particularly intrigued by the possibilities of developing weak acids that partition into hydrophobic regions of the cell membrane to act as long-acting anti- caries agents. The proposed research benefits from the combined expertise in microbial genetics and physiology and from the close interactions with those involved in other projects of the overall program.